To the Editors:

We commend the effort of these authors to undertake and report on their analysis of the QT/QTc interval during their phase I evaluation of combretastatin A4 phosphate and also for their inclusion of these data in this publication (1)
. Capturing and interpreting such data can be challenging, especially in the context of a phase I oncology study. Therefore, several aspects of this report deserve additional comment.

Study Eligibility.

Unlike phase I studies performed in normal volunteers, first-in-human studies conducted in patients with cancer are often designed to provide at least some opportunity for disease control. Should baseline QT/QTc measurements or other cardiovascular parameters exclude a patient with advanced cancer from such a first-in-human study when preclinical studies suggest that QT prolongation is a potential liability? In the study by Cooney et al.(1)
, eligibility criteria specified a “normal 12-lead ECG, reviewed by a cardiologist within 2 weeks of entry.” It would be of great interest to understand how many patients were excluded based on cardiac findings, including QTc. A small study of electrocardiogram assessments in cancer patients reported that 36% of patients have abnormalities at baseline, including sinus tachycardia, bundle branch block, ST-T wave abnormalities, atrial fibrillation, and prior myocardial infarction (2)
. In addition, it has been anecdotally reported that ∼14% of cancer patients have a prolonged QTc at baseline. However, the confounding effects of age, concomitant medicines, and underlying illnesses have not been clearly defined (3, 4)
. We need to more thoroughly explore the baseline cardiac characteristics of cancer patients so that relevant restrictions on eligibility can be carefully applied. Minimizing the number of patients excluded from participation in cancer clinical trials in which they may derive therapeutic benefit, while still ensuring safety, remains a high priority in oncology.

Variability in QT/QTc.

Understanding the intrapatient daily variability in QT/QTc is an obvious and important factor when defining what change in QTc (for an individual patient) will prompt concern or modify intended dose delivery. In a methodology study with 12-lead electrocardiograms in 32 healthy volunteers (16 males, 16 females, mean age = 38 years), the QTcF (QT corrected by the Fridericia formula) varied over the 12-hour study day bay an average of 37 milliseconds (range, 8 to 112 milliseconds; ref. 5
). Although the daily variability in QT/QTc of cancer patients has not been well described, it may be even larger because cancer patients are likely to have advanced age, concomitant medical problems and are likely to be taking concomitant medications. To reduce intrapatient variability and measurement error, it has been recommended that the baseline QT/QTc be rigorously investigated and be expressed as the mean (or median) of multiple electrocardiogram assessments, sometimes including a match in time to account for potential diurnal variation (6)
.

Correction of QT for Heart Rate.

The Bazett and the Fridericia formula are commonly used for correction of the QT interval for heart rate with the choice typically based on characteristics of the compiled data set. For example, it is known that the Bazett formula results in overestimation of the QTc at high heart rates, and the higher the heart rate, the greater the overestimate. In the study by Cooney et al.(1)
in which the Bazett formula was used, almost all of the patients had heart rates ≥ 60 bpm (23 of 25 at baseline and 24 of 24 at 4 hours), and furthermore, 11 of 24 patients had a heart rate of ≥100 bpm at 4 hours. Using the reported heart rate and uncorrected QT, we calculated the QTc using the Fridericia formula. The mean value at 4 hours after dose was 420 milliseconds, a difference of 17.5 milliseconds compared with baseline (402.5 milliseconds) as compared with their report of a more significant change (30.8 milliseconds) by the Bazett formula. Again, because the majority of the measured heart rates were ≥60 bpm, the Bazett correction may have significantly overestimated the QTc response at 4 hours. Because the optimal approach for correction depends on the data observed in the study, it is fortunate that these investigators also collected heart rate, uncorrected QT, and RR interval data, thus allowing for supplemental analyses. As the authors point out, understanding of clinical significance of their QTc findings is further complicated by lack of a placebo-treated control group, recognizing that placebo administration is commonly not acceptable to patients with advanced cancer who volunteer for phase I clinical studies (7)
.

Despite the inherent clinical trial limitations of measuring effects of drugs on QT interval, Cooney et al. achieved their study objectives and treated patients safely with a drug that likely prolongs QTc. In summary, this work adds to a new and growing experience in cancer drug development that suggests ECG monitoring can be incorporated into oncology studies to evaluate potential QT liabilities. Furthermore, the postapproval experience with arsenic trioxide, a drug known to prolong the QT interval, indicates that monitoring and risk management strategies can be designed and successfully implemented by practicing oncologists (2)
. Clearly, such liabilities should not broadly preclude development of promising new anticancer compounds. However, relative to studying potential QT prolongation in the context of cancer clinical trials, continued research is indicated to identify relevant inclusion/exclusion criteria, to determine criteria for treatment discontinuation, to identify better study designs and methodologies for QT testing, and finally, to better characterize risk-benefit considerations relative to potential QT liability and potential anticancer efficacy.

In Response:

We greatly appreciate the thoughtful comments and important insight into the challenges of electrocardiographic (ECG) monitoring and cardiac side effects that may be encountered in early phase I trials of novel anticancer agents outlined in the commentary by Varterasian et al.(1)
. They rightly point out that patients with advanced cancer are often older and therefore more likely to be receiving concomitant medications for underlying illnesses that may confound the true cardiac side effect profile of a given novel antineoplastic agent. The initial requirement for a normal ECG “signed off by a cardiologist at baseline” was prompted by the putative mechanism of action of the drug, which is a vascular targeting or, perhaps preferably, vascular disrupting agent. The true selectivity of combretastatin A4 phosphate for tumor vasculature could not be excluded on the basis of observations in preclinical animal toxicology studies and tumor blood flow models (2)
. Although an analogue of combretastin A4 phosphate, combretastatin B1, is a HERG-type K+ channel blocker and prolongs action potential duration, the cardiac electrophysiologic effects we observed with combretastin A4 phosphate, in retrospect, were not fully anticipated upon the launch of this first time in humans phase I study in cancer patients. The clinical toxicity we encountered over the course of our study was consistent with an agent that is vascularly active, substantiated by vasomotor type reactions, changes in hemodynamic parameters, abdominal and tumor pain, and cardiac ischemia (2)
. Patients were excluded for our study at entry because of abnormalities on their baseline ECG, which we did not prospectively track. We chose to correct the QT interval for changes in heart rate using the Bazett formula because this is the calculation most commonly used in clinical practice and is frequently used in clinical investigational trials despite its known limitations (3, 4)
.

We entirely agree with the comments of Varterasian et al. on the variability in QT/QTc, correction of QT for heart rate, and limitations of using the Bazett formula. Specifically, Bazett’s formula overcorrects the QT interval at fast heart rates and undercorrects it at low heart rates. The QT is negatively correlated with heart rate, and Bazett’s formula overcorrects for this by yielding a positive correlation (i.e., a situation where higher heart rates yield higher corrected QT intervals and lower heart rates yield smaller corrected QT intervals). Fridericia’s formula appears advantageous because it leaves the corrected QT interval uncorrelated with heart rate. The value of any QT measure rests, however, not with its correlation to heart rate or lack thereof but rather with its correlation to clinical toxicity. In this regard, Bazett’s metric may have as much discriminatory power as Fridericia’s metric (5)
.

The data in our study suggest that combretastin A4 phosphate has the potential to prolong Bazett’s QTc and ventricular repolarization. However, use of this agent can be done safely with appropriate surveillance and monitoring. Interestingly, the increase in heart rate observed following combretastatin may fortuitously afford protection against proarrhythmia associated with prolongation of ventricular repolarization. Torsade des pointes is associated with slow heart rates and typically occurs after bradycardic pauses. In conclusion, as we proceed with further clinical development of this compound in the phase II setting, patients are required to have normal ECGs, no history of coronary artery disease, normal left ventricular function, serum K+ and Mg2+ are monitored, and serial ECGs are obtained over the first 4 hours after infusion over the first several cycles of treatment. These safeguards are prudent, given what we presently understand about the cardiovascular safety profile of this compound while at the same time provides cancer patients with opportunities to receive a novel agent, which may ultimately prove to efficacious.